Liposomes consist of at least one lipid bilayer membrane enclosing an aqueous internal compartment. Liposomes may be characterized by membrane type and by size. Small unilamellar vesicles (SUVs) have a single membrane and typically range between 0.02 and 0.05 .mu.m in diameter; large unilamellar vesicles (LUVs) are typically larger than 0.05 .mu.m. Oligolamellar large vesicles and multilamellar vesicles have multiple, usually concentric, membrane layers and are typically larger than 0.1 .mu.m. Liposomes with several nonconcentric membranes, i.e., several smaller vesicles contained within a larger vesicle, are termed multivesicular vesicles.
Conventional liposomes are formulated to carry drugs or other active agents either contained within the aqueous interior space (water-soluble drugs) or partioned into the lipid bilayer (water-soluble drugs). As used herein, active agents "entrapped" within liposomes are those which are in the interior space of the liposome, compared to those which are partioned into the lipid bilayer and contained in the vesicle membrane itself. Active agents which have short half-lives in the bloodstream are particularly suited to delivery via liposomes. Many anti-neoplastic agents, for example, are known to have a short half-life in the bloodstream such that their parenteral use is not feasible. However, the use of liposomes for site-specific delivery of active agents via the bloodstream is severely limited by the rapid clearance of liposomes from the blood by cells of the reticuloendothelial system (RES).
The action of many drugs involves their direct interaction with hydrophobic sites within a cell, or their ability to pass through the cell membrane into cytoplasmic and nuclear compartments. These hydrophobic interactions are due to regions on the molecule that are poorly solvated by water, such that the overall aqueous solubility of the drug is compromised. One such drug is TAXOL.RTM., which has a water solubility of about 1 micromolar. The solubility of TAXOL.RTM. can be somewhat increased by chemical modification, but it is not clear how such modifications affect the function of the drug.
The efficacy of many drugs is limited by their inability to reach the intended therapeutic site. In many cases only a small fraction of the administered dose of a drug (even if water soluble) reaches the therapeutic site; most of the drug is distributed throughout the body. This distribution into healthy organs and tissues often limits dosage. Drug formulations and drug delivery methods that suspend significant amounts of a therapeutic compound is an aqueous medium, that are stabilized against dissolution in the body, and that provide for site specific delivery are therefore desirable.
The formulation of drugs with poor water solubility has traditionally focused on the use of emulsions and other association colloids, such as micelles, that dissolve the drug and therefore increase its concentration in aqueous media. However, these emulsions (and particularly micellar suspensions) are not necessarily stable and targetable to specific anatomic sites. When placed in contact with plasma or whole blood, a repartioning of drug from a micelle or emulsion into cells and macromolecular components occurs, and the drug solubilizing system no longer retains the drug.
A liposome consists of a lipid membrane surrounding an aqueous interior, and thus has the capacity to carry both water-soluble and water-insoluble drugs in its interior and its membrane, respectively. The liposome membrane, however, represents only a small part of the total volume of the total liposome construct; the capacity of a liposome to carry and release a poorly water-soluble drug in a dispersible form is limited by the small volume of the liposome membrane. The present invention optimizes the lipid composition of liposome bilayers, so that the lipid membrane can carry increased amounts of drug. The present invention also provides methods to optimize the ability of the aqueous interior to carry drug. The present invention, in particular, provides a liposome designed to carry large amounts of TAXOL.RTM..
It is accordingly desirable to devise liposome formulations capable of delivering therapeutic amounts of active agent via parenteral administration, and resulting in an extended half-life of active agent in the blood stream.